Extrinsic and intrinsic factors regulating commensal-specific T helper-17 cells

项目摘要 现在人们普遍认识到，肠道细菌在健康和疾病中发挥着重要作用。而 肠道植物群的失调已被证明有助于许多自身免疫异常，特别是 特定微生物物种与宿主免疫状态之间的关系仅在 少量的有机体。最近的研究支持了这样一种观点，即分节丝状细菌 是驱动粘膜Th 17反应的关键肠道细菌，这可以说是最重要的细菌之一。 令人兴奋的发现。然而，在发展的关键方面存在激烈的争论 粘膜Th 17细胞。利用最近开发的独特工具，我们的目标是解决三个重要问题， 问题：（1）SFB特异性Th 17细胞诱导需要哪些细胞因子;（2）SFB特异性Th 17细胞诱导需要哪些细胞因子？ 呈递细菌抗原的粘膜APC亚群;和（3）TCR的抗原亲和力如何影响 Th 17分化。这一建议的可行性得到了以下方面的支持：（1）我们开发的许多独特工具， 包括CD 4 T细胞杂交瘤、新型TCR转基因小鼠和转基因单核细胞增生李斯特菌;和（2） 我们在粘膜免疫学方面的第一手经验，特别是这个实验系统。 从该项目中获得的见解对于理解和利用粘膜免疫 应答

Project Summary   It is now widely appreciated that gut commensal bacteria play a major role in health and disease. While dysregulation of the intestinal flora has been shown to contribute to many autoimmune abnormalities, specific relationships between particular microbial species and the state of host immunity have been unraveled for only a small number of organisms. Recent studies have supported the notion that segmented filamentous bacterium is a key gut commensal bacterium for driving mucosal Th17 responses, which is arguably one of the most exciting discoveries in the field. However, there exist intense debates on key aspects of the development of mucosal Th17 cells. Taking advantage of unique tools recently developed, we aim to address three important questions: (1) Which cytokines are required for SFB-specific Th17 cell induction; (2) What are the specific mucosal APC subsets that present bacterial antigens; and (3) How does antigen affinity of TCRs impact on Th17 differentiation. The feasibility of this proposal is supported by (1) many unique tools that we developed, including CD4 T cell hybridomas, novel TCR transgenic mice and transgenic Listeria monocytogenes; and (2) our first-hand experience in mucosal immunology in general and with this experimental system in particular. Insights to be derived from this project will be important for understanding and harnessing mucosal immune responses.